The Mll4-Lsd1 Epigenetic Axis Regulates Epidermal Differentiation And Ferroptosis: Implications For Skin Cancer And Disease
Date of Award
Doctor of Philosophy (PhD)
Cell & Molecular Biology
Brian C. Capell
Epigenetic mechanisms regulate chromatin structure and gene expression to direct organismal development and tissue homeostasis, disruption of which is pervasive in cancer. Epigenetic disruption can lead to the acquisition of each hallmark of cancer and almost half of all human cancers bear mutations in epigenetic regulators. The histone methyltransferase MLL4 (KMT2D) has been described as an essential gene in both humans and mice. In addition, it is one of the most commonly mutated genes in all of cancer biology with the highest frequency of mutation occurring in cutaneous squamous cell carcinomas (cSCC). The opposing demethylase LSD1 acts in a genetic and epigenetic axis with MLL4 and is highly overexpressed in various human cancers, which has resulted in the development of highly specific and potent LSD1 inhibitors. Despite this, how the MLL4-LSD1 epigenetic axis regulates normal epidermal homeostasis or becomes dysregulated to drive cSCC tumorigenesis is not well understood. Here, using transgenic mouse models, next-generation sequencing, and human skin models, we address this gap in knowledge. First, we identify a critical role for Mll4 in the promotion of epidermal differentiation and ferroptosis, a key mechanism of tumor suppression. Mice lacking Mll4, but not Mll3 (Kmt2c), display features of impaired differentiation and human precancerous neoplasms, all of which progress with age. Mll4 deficiency profoundly alters epidermal gene expression and uniquely rewires the expression of key genes and markers of ferroptosis (Alox12, Gpx4, Slc7a11). Beyond revealing a new mechanistic basis for Mll4-mediated tumor suppression, our data uncover a potentially much broader and general role for ferroptosis in the process of differentiation and skin homeostasis. In addition to these findings, we also show that LSD1 directly represses master epithelial transcription factors that promote differentiation. LSD1 inhibitors block both LSD1 binding to chromatin and its catalytic activity, driving significant increases in H3K4 methylation and gene transcription of these fate-determining transcription factors. This leads to both premature epidermal differentiation and the repression of features squamous cell carcinoma. Together, this work reveals critical functions for the MLL4-LSD1 epigenetic axis during epidermal differentiation, ferroptosis, and tumorigenesis and offer new therapeutic strategies to be tested for the treatment of cSCC.
Egolf, Shaun, "The Mll4-Lsd1 Epigenetic Axis Regulates Epidermal Differentiation And Ferroptosis: Implications For Skin Cancer And Disease" (2022). Publicly Accessible Penn Dissertations. 5462.